Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication

• DOI: 10.1038/sj.emboj.7600597
• Publication Date: 2005-03-17T21:20:19Z
• Authors: Clodagh O'Shea; Kristina Klupsch; Serah Choi; Bridget Bagus; Conrado Soria; Jerry Shen; Frank McCormick; David Stokoe
• Keywords: DNA Replication; 0303 health sciences; TOR Serine-Threonine Kinases; Neuropeptides; Ribosomal Protein S6 Kinases, 70-kDa; Virus Replication; Adenoviridae; Cell Line; S Phase; 3. Good health; Enzyme Activation; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Protein Biosynthesis; Mutation; Phosphoprotein Phosphatases; Humans; Ras Homolog Enriched in Brain Protein; Protein Phosphatase 2; Phosphorylation; Protein Kinases; Adenovirus E4 Proteins; Monomeric GTP-Binding Proteins

Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.